Sibutramine (N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine), which is a inhibitor of 5-hydroxytryptamine and noradrenaline reuptake in vivo (Neuropharmacology, 28, p 129-134), is useful in the treatment of depression, Parkinson's disease, obesity, insulin-independent diabetes mellitus, epilepsy, and the like. In addition, sibutramine reduces body weight gain by a dual action to reduce food intake by enhancing satiety and to increase energy expenditure by stimulating heat generation (Int. J. Obesity, 19, p 145; Brit. J. Pharmacol. 114, p 388). The therapeutic use of sibutramine in depression is described in British Patent Specification 2098602. The therapeutic use of sibutramine in Parkinson's disease is disclosed in International Pat. Publication No. WO88/06444. The therapeutic use of sibutramine in cerebral function disorders is disclosed in U.S. Pat. No. 4,939,175. The use of sibutramine hydrochloride in the treatment of obesity is disclosed in European Pat. No. 397831. Also, International Pat. Publication No. WO95/20949 discloses the use of sibutramine for improving impaired glucose tolerance or glucose tolerance in patients suffering from insulin-independent diabetes mellitus.
Typically, the preparation of salts having pharmaceutically useful physical properties must satisfy the following physicochemical criteria: (1) good solubility, (2) good stability, (3) good non-hygroscopicity and (4) compressibility into tablet form.
Since sibutramine is difficult to purify due to its low melting point, it is preferable to use a crystalline material capable of being purified by recrystallization in order to prepare a pharmaceutical composition comprising sibutramine. Korean Pat. Publication No. 1990-0000274 discloses that sibutramine is utilized as salts formed with acids providing non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, in the form of hydrochloride, malate, acetate, citrate, fumarate, tartrate, succinate, aspartate or glutamate salt.
However, since sibutramine hydrochloride is difficult to handle pharmaceutically due to its hygroscopic nature, it is undesirable to use sibutramine hydrochloride for preparing medicaments. In the preparation of medicaments, a constant weight of an active compound should be contained in each dosage form, but an active ingredient absorbing water from the surrounding environment makes it difficult to achieve such consistency. Korean Patent Publication No. 94-8913 discloses that when sibutramine hydrochloride is prepared in a monohydrate form, a non-hygroscopic product is obtained, which is suitable for the preparation of capsules, tablets and other pharmaceutical dosage forms. This patent publication describes that sibutramine hydrochloride monohydrate can be prepared by contacting sibutramine hydrochloride with a medium consisting of or containing water, which is a water-immiscible solvent or a water-miscible solvent.
The currently used sibutramine hydrochloride monohydrate is prepared using a complicated process including adding a predetermined amount of water to a reaction mixture, or including preparing sibutramine hydrochloride anhydrate and suspending the sibutramine hydrochloride anhydrate in a water-containing solvent for a long time with agitation. Also, this process is disadvantageous because it is difficult to provide a precise monohydrate being not completely hygroscopic.
In this regard, intensive and through research into the development of a novel salt of sibutramine, capable of solving the problems encountered in the prior art, conducted by the present inventors, resulted in the finding that among sulphonic acid salts of sibutramine, a benzenesulfonic acid salt (besylate), a camphorsulfonic acid salt ((+)-(1S)-camphor-10-sulfonic acid salt, camsylate), a p-toluenesulfonic acid salt (tosylate) and an ethane disulfonic acid salt (1,2-ethane disulfonic acid salt, edisylate), which are in anhydrous forms not requiring a complicated procedure for preparing a hydrate containing a certain amount of water, possess good physicochemical properties (solubility, non-hygroscopicity and stability). Also, the present inventors found that a hydrous form among sulphonic acid salts of sibutramine, an ethanesulfonic acid salt (esylate) hemihydrate has remarkably high solubility in water compared to sibutramine hydrochloride monohydrate, and also exhibit non-hygroscopicity and stability.